3-[(1S,2S)-2-[2,6-bis(ethylsulfanyl)pyridin-4-yl]-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxybutyl]-2-methoxyquinoline-6-carbonitrile

• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物
• 英文名称: 3-[(1S,2S)-2-[2,6-bis(ethylsulfanyl)pyridin-4-yl]-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxybutyl]-2-methoxyquinoline-6-carbonitrile
• 化学式: C₃₃H₃₇FN₄O₃S₂
• 分子量: 620.812
• InChiKey: KJPZDCRDRIFTJI-LXANVCGNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.85
• 重原子数：
  43.0
• 可旋转键数：
  13.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  91.5
• 氢给体数：
  1.0
• 氢受体数：
  9.0

反应信息

• 作为产物：
  描述：

  2,6-二氯异烟酸 在 tris-(dibenzylideneacetone)dipalladium(0) 、 正丁基锂 、 草酰氯 、 sodium hydride 、 二异丙胺 、 N,N-二甲基甲酰胺 、 三(邻甲基苯基)磷 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 、 环己烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 54.34h， 生成 3-[(1S,2S)-2-[2,6-bis(ethylsulfanyl)pyridin-4-yl]-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxybutyl]-2-methoxyquinoline-6-carbonitrile
  参考文献：
  名称：

  Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology

  摘要：

  Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high antibacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.

  DOI：

  10.1016/j.bmc.2019.115213

文献信息

• Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology
  作者：Hamish S. Sutherland、Amy S.T. Tong、Peter J. Choi、Adrian Blaser、Scott G. Franzblau、Christopher B. Cooper、Anna M. Upton、Manisha Lotlikar、William A. Denny、Brian D. Palmer

  DOI：10.1016/j.bmc.2019.115213

  日期：2020.1

  Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high antibacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.